Patent EA-002190-B1 (EA)
Title: Process for making 2-aryl-3-aryl-5-substituted pyridines useful as cox-2 inhibitors
Inventor: PYE PHILIP J
IPC: C07D213/50
Filed: 1998-04-14
Abstract: 1. A process for making compounds of Formula I   R<1> is selected from the group consisting of (a) CH3, (b)NH2, (c) NHC(O)CF3, (d) NHCH3; Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of (a) hydrogen, (b) halo, (c) C1-4alkoxy, (d) C1-4alkylthio, (e) CN, (f) C1-4alkyl, (g) C1-4fluoroalkyl, R<2> is chosen from the group consisting of (a) F, Cl, Br, I (b) CN, (c) azide, the process comprising: condensing a compound of formula A1   under acidic conditions, and optionally in the presence of a non-reactive solvent and in the presence of an ammonium reagent, with compound A2   to yield a compound of Formula I. 2. A process according to Claim 1 wherein the nonreactive solvent is acetic acid. 3. A process according to Claim 1 wherein Ar is a mono-, di- or trisubstituted 3-pyridinyl. 4. A process according to Claim 1 wherein R<1> is CH3 or NH2. 5. A process according to Claim 1 wherein Ar is a mono- or disubstituted 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b)halo, (c) C1-3alkoxy, (d) C1-3alkylthio, (e) C1-3alkyl, (f) CF3, and (g) CN. 6. A process according to Claim 1 wherein R<1> is CH3 or NH2; and Ar is a mono- or di-substituted 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3alkyl, (d) CF3, and (e) CN. 7. A process according to Claim 1 wherein R<2> is Cl; R<1> is CH3 or NH2; Ar is a mono- substituted 3-pyridinyl and the substituents are selected from the group consisting of hydrogen and C1-3alkyl. 8. A process for making compounds of Formula I useful in the treatment of inflammation and other cyclooxygenase-2 mediated diseases.   wherein: R<1> is selected from the group consisting of (a) CH3, (b) NH2, (c) NHC(O)CF3, (d) NHCH3; Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of (a) hydrogen, (b) halo, (c) C1-4alkoxy, (d) C1-4alkylthio, (e) CN, (f) C1-4alkyl, (g) C1-4fluoroalkyl, R<2> is chosen from the group consisting of (a) F, Cl, Br, I (b) CN, (c) azide, the process comprising: (a) reacting a compound of formula A2   in the presence of a second non-reactive solvent with a strong base to yield the enolate of formula B1   wherein M is potassium, lithium or sodium, and (b) reacting a compound of formula B1 in the presence of a third non-reactive solvent with compound B2   wherein R<3> is a leaving tosyl, mesyl or halo which after heating in the presence of ammonia reagent, yields a compound of formula I. 9. A process according to Claim 8 wherein Ar is a mono- or di-substituted 3-pyridinyl. 10. A process according to Claim 8 wherein R<1> is CH3 or NH2. 11. A process according to Claim 1 wherein Ar is a mono- or di-substituted 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3alkoxy, (d) C1-3alkylthio, (e) C1-3alkyl, (f) CF3, and (g) CN. 12. A process according to Claim 8 wherein R<1> is CH3 or NH2; and Ar is a mono- or di-substituted 3-pyridinyl and the substituents are selected from the group consisting of (a) hydrogen, (b) halo, (c) C1-3alkyl, (d) CF3, and (e) CN. 13. A process according to Claim 8 wherein R<2> is Cl; R<1> is CH3 or NH2; Ar is a mono-substituted 3-pyridinyl and the substituents are selected from the group consisting of hydrogen and C1-3alkyl. 14. A process according to Claim 1 wherein R<2> is chloro. 15. A process according to Claim 8 wherein R<3> is chloro. 16. A process according to Claim 1 or 8 wherein the ammonium reagent is selected from ammonia and ammonium acetate. 17. A process according to Claim 8 wherein the strong base is lithium bis(trimethylsilyl)amide. 18. A process according to Claim 8 wherein the third nonreactive solvent is toluene.